Under certain conditions, including in certain disease states, an individual's immune system will identify its own constituents as “non-self”, and initiate an immune response against “self” material, at times causing more damage or discomfort as from an invading microbe or foreign material, and producing serious illness in an individual. Autoimmune disease results when an individual's immune system attacks his or her own organs or tissues, producing a clinical condition associated with the destruction of that tissue, as exemplified by diseases such as rheumatoid arthritis (RA), insulin-dependent diabetes mellitus, acquired immuno-deficiency syndrome (“AIDS”), hemolytic anemias, rheumatic fever, Alzheimer's disease, asthma, atherosclerosis, inflammatory bowel disease, ischemic injury, Parkinson's disease, myasthenia gravis, anemia, scleroderma, Addison's disease; septic shock, psoriasis, thyroiditis, glomerulonephritis, autoimmune hepatitis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), etc. Blocking, neutralizing or inhibiting the immune response, counteracting the consequences of the immune activity or removing its cause in these cases is, therefore, desirable.
It is believed that rheumatoid arthritis results from the presentation of a relevant antigen to an immunogenetically susceptible host. The antigens that could potentially initiate an immune response that results in rheumatoid arthritis might be endogenous or exogenous. Possible endogenous antigens include collagen, mucopolysaccharides and rheumatoid factors. Exogenous antigens include e.g. mycoplasms, mycobacteria, spirochetes and viruses. By-products (e.g. prostaglandins and oxygen radicals) of the immune reaction inflame the synovium and trigger destructive joint changes (e.g. collagenase). Rheumatoid arthritis (involving the destruction of the joint lining tissue) are characterized as being the result of a mostly cell-mediated autoimmune response and appear to be due primarily to the action of T-cells (see Sinha et al., Science 248:1380 (1990)).
There is a wide spectrum of disease severity, but many patients run a course of intermittent relapses and remissions with an overall pattern of slowly progressive joint destruction and deformity. The clinical manifestations may include symmetrical polyarthritis of peripheral joints with pain, tenderness, swelling and loss of function of affected joints, morning stiffness, and loss of cartilage, erosion of bone matter and subluxation of joints after persistent inflammation. Extra-articular manifestations include rheumatoid nodules, rheumatoid vasculitis, pleuro-pulmonary inflammations, scleritis, sicca syndrome, Felty's syndrome (splenomegaly and neutropenia), osteoporosis and weight loss (Katz (1985), Am. J. Med., 79:24 and Krane and Simon (1986), Advances in Rheumatology, Synderman (ed.), 70(2):263-284). The clinical manifestations will result in a high degree of morbidity resulting in disturbed daily life of the patient. Unfortunately, despite considerable investigative efforts there is no cure for RA.
Established treatments of RA are designed to inhibit either final common pathways of inflammation or immunological mediators. Both approaches are non-specific and, therefore, are associated with severe side effects. Corticosteroids have multiple effects on the immune system and other tissues. Their use is complicated by very high incidence of musculoskeletal, metabolic, neurologic and connective tissue side effects, as well as immunosuppression which may lead to life-threatening infections. For this reason, corticosteroids are usually avoided until all other forms of treatment have failed. See generally, R. Million et al., “Long-Term Study of Management of rheumatoid Arthritis”, Lancet 1:812 (1984).
Cytotoxic and anti-metabolic drugs, such as methotrexate, azathioprine and cyclophosphamide are non-specifically affecting all rapidly dividing cells and therefore are associated with bone marrow and gastrointestinal toxicity and increased incidence of malignancy. In addition, methotrexate treatment of RA has been reported to induce liver damage and lung disease which may be fatal. See J. A. Engelbrecht et al., “Methotrexate Pneumonitis After Low-Dose Therapy for Rheumatoid Arthritis”, Arthritis and Rheumatism 26:1275 (1983) and G. W. Cannon et al., “Acute Lung Disease Associated With Low-Dose Pulse Methotrexate Therapy In Patients With Rheumatoid Arthritis”, Arthritis and Rheumatism 26:1269 (1983).
Most nonsteroidal anti-inflammatory drugs (NSAIDs) currently used are designed to non-specifically inhibit prostaglandin synthesis. NSAIDs currently in use modify or diminish—but to not arrest—the inflammatory response. Acetyl salicylic acid remains the most commonly used NSAID. Acetyl salicylic acid toxicity takes many forms, including hypersensitivity reactions, deafness, gastrointestinal and renal toxicity. See generally Simon and Mills, “Nonsteroidal Antiinflammatory Drugs”, N. Eng. J. Med. 302:1179 (1980).
Gold compounds and penicillamine have also been used in the treatment of RA. They are both associated with high incidence of bone marrow, renal and mucocutaneous toxicity. Gold treatment, in particular, is associated with nephropathy, W. Katz et al., “Proteinuria in Gold-Treated Rheumatoid Arthritis”, Ann. Int. Med. 101:176 (1984), Penicillamine, while questionably effective, is toxic even at relatively low doses. See W. F. Kean et al., “The Toxicity Pattern Of D-Penicillamine Therapy”, Arthritis and Rheumatism 23:158 (1980). These problems have led to almost complete abandonment of these drugs in RA therapy.
Other established therapies are cyclosporin and anti-TNF.alpha-antibodies. However, serious renal toxicity and non-specific immunosuppression limit significantly the utility of cyclosporin. Due to its ubiquitous role in many cellular functions, anti-TNF therapy may not be a safe therapeutic strategy for RA. Development of lupus-like disease has been noticed in some cases. However, clinical efficacy data show promising results with the anti-TNF approach.
Thus, current therapies for RA are associated with high incidence of serious side effects. Furthermore, although some medications may offer symptomatic relief, in many cases, they do not significantly modify the progression of joint destruction. What is needed is an effective therapeutic approach with lower toxicity such that the treatment is better tolerated and more appropriate for the treatment of RA.
The present invention contemplates a new class of anti-RA drug, namely compounds that produce a reduction in the clinical signs and symptoms of the disease.
Multiple sclerosis (MS) is a disease of the central nervous system that affects the brain and spinal cord. It strikes an estimated 2.5 million people worldwide and is the major acquired neurologic disease in young adults. With destruction of the protective myelin sheath, nerve impulses are disrupted leading to a variety of neurological symptoms. Common signs and symptoms of MS include fatigue, psychological and cognitive changes, weakness or paralysis of limbs, numbness, vision problems, speech difficulties, muscle spasticity, difficulty with balance when walking or standing, bowel and bladder dysfunction, and sexual dysfunction. Approximately half the people with this disease have relapsing-remitting MS in which there are unpredictable attacks where the clinical symptoms become worse (exacerbation) which are separated by periods of remission where the symptoms stabilize or diminish. The other half have chronic progressive MS without periods of remission.
At present there are no cures for MS. Many medications are available to relieve symptoms in progressive MS. For example, corticosteroids are used to reduce inflammation in nerve tissue and shorten the duration of flare-ups; Muscle relaxants such as tizanidine (Zanaflex) and baclofen (Lioresal) are oral treatments for muscle spasticity; Antidepressant medication fluoxetine (Prozac), the antiviral drug amantadine (Symmetrel) or a medication for narcolepsy called modafinil (Provigil) are used to reduce fatigue.
A few other drugs are available for MS that are not directly related to symptom management but may act to alter the course of the disease. These drugs include beta interferons (Betaferon, Avonex, Rebif) and glatiramer acetate (Copaxone). These drugs may have an impact on the frequency and severity of relapses, and the number of lesions as seen on MRI scans. Some of the drugs appear to have an effect of slowing the progression of disability. U.S. Pat. No. 4,617,319 discloses a method of treating multiple sclerosis using 1,4-dihydroxy-5,8-bis[[(2-hydroxyethylamino)ethyl]amino]anthraquinone, which is also known by the generic name mitoxantrone (Novantrone).
None of these existing therapies are proven satisfactory because of limited efficacy and/or significant toxicity. In addition, many of these therapies are required to be administered frequently and some are very expensive. Thus, there clearly exists a need for novel and effective methods of treating MS.
The compounds of the present invention may be formulated for oral, parenteral (e.g. intravenous, intramuscular or subcutaneous), dermal, buccal, intranasal, sublingual or rectal administration or may be formulated for administration by inhalation or insufflation. Furthermore, the compounds according to the present invention may also be formulated for sustained delivery.